National Institute of Neurological Disorders and Stroke (NINDS)
National Center for Complementary and Integrative Health (NCCIH)
National Cancer Institute (NCI)
National Eye Institute (NEI)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
National Institute on Drug Abuse (NIDA)
National Institute of Dental and Craniofacial Research (NIDCR)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institute of Nursing Research (NINR)

The purpose of this funding opportunity announcement (FOA)
is to invite applications for the Specialized Clinical Centers (“hubs”) of
the Early Phase Pain Investigation Clinical Network (EPPIC-Net). EPPIC-Net
will serve as the cornerstone of the NIH’s Helping to End Addiction Long-term
(HEAL) Initiative. EPPIC-Net will provide a robust and readily
accessible infrastructure for carrying out in depth phenotyping and biomarker
studies in patients with specific pain conditions, and the rapid design and
performance of high-quality Phase 2 clinical trials to test promising novel
therapeutics for pain from partners in academia or industry. Studies will
bring intense focus to patients with well-defined pain conditions and high
unmet therapeutic needs.

EPPIC-Net will consist of one Clinical Coordinating Center
(CCC), one Data Coordinating Center (DCC) and approximately 10 specialized
clinical centers (“hubs”). The purpose of this funding opportunity
announcement (FOA) is to invite applications for the hubs within EPPIC-Net. A
hub will typically be a regional medical center that will actively enroll
subjects into clinical trials and studies performed in EPPIC-Net. Each hub
should have ready access to patient populations with specific pain conditions
and have expertise in characterization of that pain condition. A hub will
additionally provide scientific leadership and administrative oversight to
its multiple (2-10) satellite sites (“spokes”).

This FOA solicits applications EPPIC-Net Specialized
Clinical Centers. Separate FOAs have been issued to solicit applications for
the Clinical Coordinating Center (RFA-NS-19-023) and Data Coordinating Center
(RFA-NS-19-024). Clinical trials conducted through EPPIC-Net may come from a
variety of sources including the HEAL Partnership, as described above, or
from separate NIH funding announcements.

Key Dates

Posted Date

December 10, 2018

Open Date (Earliest Submission Date)

January 6, 2019

Letter of Intent Due Date(s)

30 days prior to the application due date

Application Due Date(s)

February 6, 2019, by 5:00 PM local time of applicant
organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on this date.

No late applications will be accepted for this Funding
Opportunity Announcement

Applicants are encouraged to apply early to allow adequate
time to make any corrections to errors found in the application during the
submission process by the due date.

AIDS Application Due Date(s)

Not Applicable.

Scientific Merit Review

March 2019

Advisory Council Review

May 2019

Earliest Start Date

July 2019

Expiration Date

February 7, 2019

Due Dates for E.O. 12372

Not Applicable

Required
Application Instructions

It is critical that applicants follow the Research (R) Instructions
in the SF424
(R&R) Application Guide, except where instructed to do otherwise (in
this FOA or in a Notice from the NIH
Guide for Grants and Contracts). Conformance to all requirements (both
in the Application Guide and the FOA) is required and strictly enforced. Applicants
must read and follow all application instructions in the Application Guide as
well as any program-specific instructions noted in Section IV. When the program-specific
instructions deviate from those in the Application Guide, follow the
program-specific instructions. Applications that do not comply with
these instructions may be delayed or not accepted for review.

There are several options available to submit your application through Grants.gov to NIH and
Department of Health and Human Services partners. You must use one of these submission
options to access the application forms for this opportunity.

Use the NIH ASSIST system to prepare, submit and track your application online.

The purpose of this funding opportunity announcement (FOA)
is to invite applications for the Clinical Coordinating Center (CCC) of the
Early Phase Pain Investigation Clinical Network (EPPIC-Net). EPPIC-Net will
serve as the cornerstone of the NIH’s Helping to End Addiction Long-term (HEAL)
Partnership. EPPIC-Net will provide a robust and
readily accessible infrastructure for the rapid implementation and performance
of high-quality, comprehensive studies of patients with well-defined pain
conditions, and the rapid design and performance of high-quality Phase 2
clinical trials to test promising novel therapeutics for pain. Studies will
bring intense focus to relatively small numbers of patients with clinically
well-defined pain conditions and high unmet therapeutic needs. Studies may be
performed in either adult or pediatric populations. The network will be charged
with testing novel, efficient study designs including adaptive and
platform designs, validation studies of biomarkers, and biomarker-informed
proof of principle or target engagement studies in phase 2 trials of
interventions from academic and industry partners. EPPIC-Net will make clinical, neuroimaging, biomarker, and
preclinical data, as well as biosamples, available through public access data
and biospecimen repositories. It is anticipated that EPPIC-Net will be able to
run at least as five Phase 2 trials concurrently, in addition to deep clinical
phenotyping and biomarker validation studies.

EPPIC-Net will consist of one Clinical Coordinating Center
(CCC), one Data Coordinating Center (DCC) and approximately 10 specialized
clinical centers (“hubs”). The purpose of this funding opportunity announcement
(FOA) is to invite applications for the hubs within the network. A hub will
typically be a regional medical center that will actively enroll subjects into
clinical trials and studies performed in EPPIC-Net. Each hub should have ready
access to patient populations with specific pain conditions and have expertise
in their characterization. A hub will additionally provide scientific
leadership and administrative oversight to its multiple (2-10) satellite sites
(“spokes”).

Clinical studies may come to the network from two sources:

(1) Clinical trials to test the
efficacy of therapeutic candidates (“assets”) such as small molecules,
biologics, and medical devices as contributed by academic or industry partners.
More details on this are outlined in the “Network Projects” and “Significant
responsibilities of the CCC” sections below.

(2) Clinical research studies aimed at understanding the
biological basis of different pain states or validation of biomarkers for their
utility in phase 2 studies. These studies would result from forthcoming FOAs
from NIH.

Clinical studies may not be limited to these two sources, so
EPPIC-Net must be flexible enough to incorporate studies from other sources as
directed by the NIH.

Background

This program is part of the NIH
Helping End Addiction Long-term (HEAL) Initiative, an effort to speed
scientific solutions to stem the national opioid public health crisis. Opioid
overdose deaths reached more than 42,000 annually in 2016 and more than 2 million
Americans are addicted to opioids. There are also 25 million people, or 11% of
the U.S. population, who experience daily chronic pain, many of whom are
prescribed opioids for pain management. New treatment options for pain are
needed to reduce the number of people exposed to the risks of opioids.

There is a clear public health imperative to stimulate and
support research that improves the care and outcomes of patients with severe
acute and chronic pain. The Federal
Pain Research Strategy, published in 2017, identified the development of
safer non-opioid analgesics as a top priority and specifically noted the need
for the discovery and validation of new pharmacologic and non-pharmacologic
targets for the treatment of pain. This was also identified as a priority in a
series of cross-cutting meetings that convened experts from across government,
industry, and academia to determine the high priority areas that could be addressed
by a partnership across all sectors. There is a critical need for development
of non-opioid pharmacologic and non-pharmacologic treatments for pain. It is
also essential to study treatments that reduce the psychosocial and existential
burden of pain associated with chronic medical illnesses such as cancer,
complex regional pain syndrome, pancreatitis, polycystic kidney disease,
headache and other craniofacial pain disorders, pelvic pain disorders,
fibromyalgia, diabetic and chemotherapy related neuropathy, and sickle cell
disease.

Low back pain represents an area of special interest for
this FOA. According to National Health Interview Survey data, 20% of adults in
the United States reported “frequent” back pain and 28% of adults experienced
low back pain that lasted a whole day or more during the previous three months.
Out of all 291 conditions included in the Global Burden of Disease 2010 Study,
low back pain ranked highest in terms of years lived with disability. It is a
tremendous public health and economic burden as well as a major contributor to
the use of opioids in the US. Some non-opioid treatments appear to have mild to
moderate effects on chronic back pain and function in some patients, and
combination therapies are, in general, more effective than monotherapies.
Currently there is no effective treatment that provides long term, sustained
relief of back pain and disability for all patients.

In addition, there is an urgent need to optimize, and
validate objective mechanistic biomarkers associated with pain conditions. It
is also necessary to better understand the different biologic mechanisms that
underly different pain conditions, as well as the mechanisms that tie common
overlapping pain conditions together, through the intense clinical phenotyping
of patients with specific pain conditions. This will enrich clinical study
populations by allowing or improving cohort stratification, providing
predictors of treatment responses, and demonstrating engagement of the
therapeutic target.

To address these needs, EPPIC-Net will incorporate
innovative designs to accelerate therapy development in well-phenotyped subpopulations of patients with
well-characterized pain conditions. EPPIC-Net will perform comprehensive
studies of the biologic basis of specific pain conditions, biomarker validation
studies, and Phase 2 clinical trials to test interventions for their potential
as efficacious, non-addicting treatments for acute and chronic pain.

Research Objectives

EPPIC-Net will harness
multidisciplinary clinical, statistical, and data management expertise to
provide the scientific leadership and infrastructure required to design and
conduct multi-site Phase 2 clinical trials, biomarker validation studies, and
deep phenotyping of patient populations to understand the biologic basis of a
specific pain condition and its response to treatment. The overall goal is to
accelerate development of non-addictive therapies for adult or pediatric
patients with acute and/or chronic pain. Due to the
enormous disease burden of low back pain (as outlined in the background), one
further research objective of EPPIC-Net is to dissect the structures and
mechanisms involved in chronic low back pain as well as to identify, prioritize
and test new therapies targeted to these specific mechanisms.

The hubs will contribute to these objectives by conducting
clinical trials and biomarker validation studies. The hubs will also work with
the EPPIC-Net CCC and investigators from the NIH HEAL Partnership to develop
and execute clinical trials based on meritorious assets, as described elsewhere
in this FOA. PDs/PIs at the hubs will serve as experts to develop
biomarker-informed phase 2 clinical trial protocols matched to the specific
asset. The clinical protocols will be targeted to defined pain conditions will
be designed to ascertain whether the intervention meets pre-specified go/no-go
criteria for progressing to later stage development (i.e., Phase 3
industry-supported trials). The CCC will work closely with the PD/PI from the
hub with expertise most closely aligned with the target patient population for
the asset, to develop a clinical protocol matched to that asset (or an ad hoc
hub if need be). If deemed meritorious by NIH peer review, the PDs/PIs at the
hubs will work with the CCC to execute the clinical trial.

Due to the vast disease burden of low back pain (as outlined
in the background), one further research objective of EPPIC-Net is to dissect
the structures and mechanisms involved in chronic low back pain as well as to
identify, prioritize and test new therapies targeted to these specific
mechanisms.

EPPIC-Net Organization

The EPPIC-Net will be
funded by NIH, with NINDS as the lead institute. As described above,
EPPIC-Net will consist of one CCC, one DCC, and up to 10 hubs with affiliated
satellite spokes, with the capability to coordinate clinical research across
different pain conditions in a large number of clinical centers across the
United States.

The Clinical
Coordinating Center (CCC) will provide scientific and organizational leadership
to EPPIC-Net to achieve both efficiency and excellence in its implementation
and performance of clinical trials. Responsibilities of the CCC will
specifically include coordinating and managing the EPPIC-Net central IRB,
establishing and managing master contract agreements with the clinical sites
for trial performance, developing recruitment plans, coordinating investigator
and coordinator training, tracking enrollment and overseeing quality
improvement. The roles and responsibilities of the CCC are described more fully
in RFA-NS-19-023.

The Data Coordinating Center (DCC) will provide
scientific and organizational leadership to EPPIC-Net in all aspects of data
management, data quality, statistical design, statistical analysis, and through
managing repositories for biosamples, clinical, neuroimaging, biomarker, and
omics data. Responsibilities of the DCC particularly include management and
support of the Data and Safety Monitoring Board (DSMB), and reporting to
regulatory authorities (e.g., central IRB, FDA). The role and responsibilities
of the DCC are described in RFA-NS-19-024.

The Specialized Clinical Centers
(hubs) will provide scientific leadership and conduct clinical trials,
prospective observational studies, and biomarker validation studies in the
clinical centers. A hub is envisioned as a regional academic medical center
that will enroll patients directly and provide clinical and organizational
leadership to its network of 2-10 satellite spokes that will also enroll
patients. Each hub must be capable of recruiting physicians and investigators for studies in a variety of pain
conditions therefore requiring broad pain expertise within the hub and spokes
(e.g., neurology, rheumatology, obstetrics/gynecology, oncology, pediatrics,
orthopedics, gastroenterology, or other subspecialty) and have access to
clinical populations from a wide variety of pain conditions. The roles and
responsibilities of the hubs and spokes are described more fully below. In
order to include the appropriate expertise on a given study or trial, EPPIC-Net
will have the ability to include additional ad hoc hubs or spokes.

The CCC, DCC, hubs and spokes are each integral components
of the network. The success of the network will require close, active
cooperation and collaboration to assimilate these elements into a highly
effective clinical research structure. Participants at all levels in EPPIC-Net
are strongly encouraged to promote innovative methods to improve efficiency and
quality in performance of clinical research. Additionally, the HEAL Partnership
will enable consultation with representatives from industry, academia and pain
related non-profit organizations.

The FOAs for the CCC, DCC, and hubs will support cooperative agreements, under
which the awardees will be expected to achieve previously agreed-upon
milestones and metrics, as described in each of the FOAs.

Network Projects

Generally, appropriate clinical
trials will be phase 2 trials to test novel drugs, biologics, and devices. It
is possible that this could expand to natural products, surgical, or
non-pharmacological interventions. EPPIC-Net will also incorporate studies
including biomarker discovery and validation, and clinical studies to uncover
underlying biologic mechanisms in specific pain conditions. In the planning
phases of these studies, the CCC may be directed by NIH to work with the hub
and satellite spokes to collate information about patients with pain conditions
and perform deep phenotyping and clinical characterization.

More specifically, it is envisioned that clinical studies
may come to the network in two ways:

(1) Academic or industry partners
within the HEAL Partnership may propose clinical trials to test the efficacy of
therapeutic candidates (e.g., novel drugs, biologics, and devices; “assets”).
These assets and trial protocols will be scientifically reviewed and
prioritized prior to entering the network by NIH peer review. Expertise from
the hubs will be critical in designing clinical trials around the highly
prioritized assets. More details on this process are outlined below in
“Significant responsibilities of the CCC.”

(2) Applications for clinical research studies aimed at
understanding the underlying biologic mechanisms of different pain states or
validation of biomarkers for their utility in phase 2 studies will be solicited
through forthcoming FOA(s). NIH support of such studies will include additional
funding for the CCC and other network components to coordinate the research
with the study PI.*

*Note that NIH anticipates that the first
examples of these kinds of studies will be focused on a patient-centric
translational research program in low back pain. The goal of these studies will
be to probe the biomedical mechanisms of low back pain in a biopsychosocial
context using interdisciplinary methods and innovative technologies, so that
novel treatments can be developed, tested and combined for a targeted,
integrated and individualized approach to treatment.

Clinical studies may not be limited to these two sources, so
EPPIC-Net must be flexible enough to incorporate studies from other sources in
forthcoming FOAs as directed by the NIH. EPPIC-Net is intended as a
multidisciplinary network reflective of the spectrum of clinical challenges
confronted in pain management. Candidate therapies tested through clinical
trials may come from academic investigators, investigators in military medical
facilities, small business, industry, or other eligible institutions. The
network may also be called upon to join or engage in other, on-going clinical
trials in pain medicine. EPPIC-Net should be prepared to work collaboratively
with other programs or networks, as a lead, partner or participant, as
appropriate.

Hubs: Characteristics, Roles and Responsibilities

A typical EPPIC-Net Clinical hub is envisioned as a medical center with full
multidisciplinary coverage (24/7) such as 1) a major pain referral center or 2)
a tertiary care facility or health care system that cares for patients with a
wide variety of pain conditions. A hub must function as an exemplary clinical
research site itself, while concurrently providing leadership, organizational
oversight and research support of its spokes.

Each hub must be able to:
1) Execute Phase 2 trials;
2) provide and coordinate the multiple specialties that may participate in
the trials, such as neurology, anesthesiology,
rheumatology, obstetrics/gynecology, oncology, pediatrics, orthopedics,
physical medicine, gastroenterology, or other subspecialties providing care to
patients with pain; and
3) propose and oversee a network of spokes.

Each hub must have a flexible network of spokes. The
principal function of the spokes is to provide access to a larger patient
population for trial enrollment. Spokes also increase access to patients with a
particular pain condition, to patients from underserved communities to enhance
diversity, or complement the hub by providing access to specific research or
clinical expertise. For each clinical trial, the hub would be expected to
construct a network of 2-10 spokes specifically tailored to the needs of that
particular trial. Since the requirements of each clinical trial will be
somewhat different, the identity and configuration of spokes will be unique for
each trial. Therefore, a hub should have relationships with a number of potential
spokes, and the ability to add spokes as appropriate. To demonstrate the
ability to attract spokes, the applicant is requested to identify in the grant
submission potential spoke sites committed to participation in at least one
clinical trial. The hub may need to have plans and mechanisms for recruiting
and adding other spokes, when needed.

The hub and spokes together must be able to 1) support recruitment of at least
100 well-phenotyped subjects with specific pain conditions per year into
concurrent phase 2 trials (exact subject numbers may be different per the
milestones in any specific trial), and; 2) provide physicians who are experts
in the fields of neurology, anesthesiology, rheumatology,
obstetrics/gynecology, oncology, pediatrics, orthopedics, physical medicine,
gastroenterology, or other subspecialties providing care to patients with pain.
Additional expertise may also be required. Spokes may range from academic pain
treatment centers to community hospitals, or other applicable health care settings
and networks to expand patient access and representation of minority, rural and
other segments of the population. The spokes may be geographically related
partnering medical centers or geographically distant centers where productive
collaboration have been well established. Spokes should be located in North
America. Spokes may enroll and treat patients on-site or may identify patients
to transfer to the hub for enrollment. There is no ideal or preferred
arrangement.

Since the design and requirements will be unique for each meritorious clinical
trial, EPPIC-Net must be flexible. Hubs should be resourceful and
innovative in approaching the challenges of each study. Examples of some
variations that may occur include, but are not limited to:

- Participant age (adult only studies as well as with
children or adolescents, if appropriate for the pain condition);

Milestones will be determined at the
time of award. Failure to meet the agreed upon milestones may result in reduced
or restricted funding or early termination of the cooperative agreement (see
Cooperative Agreement Terms and Conditions of Award).

Significant responsibilities of the hubs include the
following:

a) Clinical trial protocol
development and execution on therapeutic assets.

A separate FOA will be used to allow prioritization of assets
prior to being tested in the network. Of those that are deemed meritorious, the
CCC will receive information on the assets and work with the asset-owner to
solicit expertise from the various hubs (or ad hoc sites, if needed) to develop
biomarker-informed phase 2 clinical trial protocols matched to the specific
asset. The CCC will receive information on the asset in the form of a dossier
that will contain information on preclinical, clinical, and pharmacological data.
A hub PD/PI will be identified by the CCC whose expertise is closely aligned
with the target patient population for the asset. This hub PD/PI will serve as
the PI for the trial. (If appropriate expertise is not available within the
network, the CCC may have to recruit expertise from an ad hoc site to serve as
“protocol PI” for a given clinical trial.) The CCC will provide guidance and
serve as the coordinator between the asset-owner and the protocol PI from the
hub.

The clinical protocols will be targeted to defined pain
conditions in deeply phenotyped cohorts and will be designed to ascertain
whether the intervention meets pre-specified go/no-go criteria for progressing
to later stage development (i.e., Phase 3 industry-supported trials). The hub
PD/PI who designed the protocol will work with the CCC to submit the
asset-matched clinical protocol back to NIH for peer review. This clinical
trial protocol should be in the form of the standard template as outlined in NOT-OD-17-064.
Of the clinical studies that are deemed highly meritorious by peer review, the
hubs and spokes will carry out the clinical trial as designed in the protocol.

b) Studies on low back pain. As NIH anticipates a forthcoming
set of studies as part of the Back Pain Consortium (BACPAC) Research program,
BACPAC is focused on chronic low back pain research using novel, inter and
multidisciplinary integrated approaches and novel analytics for discovery of
disease mechanisms and features for deep patient phenotyping and identification
of new targets for intervention. More information can be found in the following
notices: NOT-AR-19-022, NOT-AR-19-023, NOT-AR-19-024,
and NOT-AR-19-025.
The hubs will be expected to recruit patients for the following kinds of
studies:

- Phase 2 trials of new drugs, biologics, devices,
and physical interventions, particularly those that arise from new
understandings of mechanisms of back pain;

- Adaptive clinical trials based on the results of
the longitudinal studies.

While the hubs will be expected to have access to patient
populations with chronic low back pain, further information on this research
program will be available in forthcoming FOAs.

c) Master Contracts and Payments will be used to speed
implementation of clinical trials in the EPPIC-Net. The CCC will negotiate
and maintain a master contract with each hub and each spoke. Payments will be
on a per-patient basis, according to clinical trial budgets and the master
trial agreement, and will be directly distributed by the CCC to each hub and
spoke. All clinical centers, both hubs and spokes, are expected to work
cooperatively with the CCC and to accept the master contract and payment
system. Applicants are encouraged to consult with their institutions regarding
acceptability of master contracts. Applicants who cannot accept master contracts
and payments will be considered non-responsive to this FOA.

d) Central Institutional Review Board (IRB). The CCC will implement
and manage a central IRB for the EPPIC-Net and will create reliance agreements
with each hub and spoke. All the clinical centers must use the central IRB for
standard clinical trials. The hubs will use the central IRB for
EFIC studies, though fulfillment of community-based requirements may entail
collaboration with local IRBs, local community liaisons, local community representatives
or other means.

e) Patient Enrollment In cooperation with the CCC, the
hubs are responsible for creating and executing clinical trial-specific patient
recruitment plans for itself and its spokes. Achievement of recruitment
goals for diverse and underserved populations (i.e., ethnic groups, racial
groups, gender, rural populations) is particularly important. If
recruitment is not meeting expectations, the hub, in cooperation with the CCC,
must create and successfully execute a corrective action plan(s) to continue
participation in EPPIC-net.

f) Quality Assurance The hub is responsible for quality
control and improvement for itself and its group of spokes. The CCC has broader
responsibility for creation and monitoring of specific, quantifiable performance
metrics for the EPPIC-Net, which will likely include start-up time, patient
recruitment and retention, time from last patient last visit to database lock,
and number and aging of data queries. Quality reviews will be performed at
least annually. Hubs and spokes are expected to cooperate with the CCC in
quality reviews and are further encouraged to propose innovative approaches to
quality assessment and improvement.

g) EPPIC-Net Governance Committees. The hub PD/PI or designee is expected
to actively participate in the EPPIC-Net Steering Committee (ENSC) and to serve
on a rotating basis on the EPPIC-Net Management Committee (ENMC) and the
EPPIC-Net Operations Committee (ENOC). The governance committees and
anticipated meeting frequency are described at the end of this section.

The responsibilities of the EPPIC-Net hubs include but are
not limited to:

- Identifying and recruiting spokes, including altering or
adapting its spoke network to the particular needs of each clinical
trial;

- Providing the spokes with clinical leadership, research
support, guidance and oversight for the EPPIC-Net processes and procedures
and regular communication regarding status of the EPPIC-Net and individual
clinical trials;

- Implementing trials at the hub and spoke sites, involving,
but not limited to: 1) assembling local research team(s), 2) training the
spokes on EPPIC-Net and trial procedures, 3) assuring protocol adherence, 4)
recruiting, treating, and following patients according to the study protocols,
and 5) collecting and entering accurate, high quality data and biosamples into
the central data management system and repositories as run by the DCC.

- Retaining participants throughout the follow-up period as
required by protocol;

- Ensuring adequacy of human subjects' protections;

- Tracking and reporting trial and performance data to the
CCC and/or DCC on a regular and frequent basis, including recruitment,
retention, and adverse events, as required per protocol and by the IRB;

- Providing complete, accurate, and timely data entry, as
well as rapid and complete resolution of any data queries, and a high level of
data quality and completeness to the DCC.

- Specifically, hub PD/PIs or designees are expected to
provide scientific viewpoints and expertise on the breadth of issues discussed
in the above venues, especially in the design of phase 2 trials for novel
treatments in specific pain conditions.

- Participating in authorship of manuscripts and public
dissemination of project results, as appropriate;

- Applicants are specifically encouraged to interact with
the Clinical and Translational Science Award (CTSA), if present at their
institution, to identify resources. This may include access to or assistance
from Recruitment (RIC) and Trial (TIC) liaisons at the CTSA.

- Promoting visibility and awareness of the EPPIC-Net within
the Institution and the larger pain research community;

- Increasing and disseminating knowledge about pain research
at the hub and spokes to medical students, residents, fellows, allied health
professionals and nurses when feasible. Helping new investigators develop
skills and experience to progress to more senior or experienced status, when
appropriate.

The EPPIC-Net Management Committee (ENMC) and the EPPIC-Net
Operations Committee (ENOC) oversee the day-to-day administration and
operations of EPPIC-Net. The first is more oriented towards strategic and
administrative functions, the second towards operational and executional functions.
Each clinical trial will have a Trial Committee, responsible for conduct
of that particular trial.

Clinical trial PD/PI (chair), CCC and DCC research team
members (one of which should be either the CCC PD/PI or DCC PD/PI)

Monthly by phone or webinar, adjusted by activity and
needs of trial

* Hub PDs/PIs or designees will serve on a rotating basis,
with attention to balance across specialties (e.g., neurology, rheumatology, orthopedics)

As part of the HEAL
Initiative, federal oversight will be provided by the HEAL EPPIC-Net
Federal Committee, which will consist of leadership and staff from the NIH HEAL
Initiative Institutes. NINDS is the lead institute for the EPPIC-Net infrastructure
of CCC, DCC, and clinical Hubs, but there will be substantial involvement from
other NIH Institutes and Centers. NIH will provide at least one member to
participate on the ENSC, ENMC, and ENOC. Independent of the governance above,
the NINDS Director retains oversight for all funded research from individual
institutes or programs. The Directors’ authority overrides all ENSC, ENMC, and
ENOC decisions.

It is also anticipated that the
governance committees of EPPIC-Net will have significant interaction with other
HEAL Initiative coordinating committees made up of representatives from
academia, industry, government, and the patient advocacy community.

Cooperative Agreement: A support mechanism used when there
will be substantial Federal scientific or programmatic involvement.
Substantial involvement means that, after award, NIH scientific or program
staff will assist, guide, coordinate, or participate in project activities. See
Section VI.2 for additional information about the substantial involvement for
this FOA.

Application Types Allowed

New

The OER
Glossary and the SF424 (R&R) Application Guide provide details on
these application types.

Clinical Trial?

Not Allowed: Only accepting applications that do not
propose clinical trials

NINDS intends to commit up to approximately $2,800,000 in
FY 2019 to fund 10 total awards. Future year amounts will depend on annual
appropriations, but NIH expects to maintain the hubs at the same funding
level through 2023.

Award Budget

Application budgets need to reflect the actual needs of
the proposed project and are limited to $150,000 in direct costs for each
year of the project period. As a cooperative agreement, NIH funds are
contingent upon success of meeting milestones and the budget may be
renegotiated to reflect the needs of the network and NIH priorities.

Award Project Period

5 years

NIH grants policies as
described in the NIH
Grants Policy Statement will apply
to the applications submitted and awards made from this FOA.

Section III. Eligibility
Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

Public/State Controlled Institutions of Higher Education

Private Institutions of Higher Education

The following types of Higher Education Institutions
are always encouraged to apply for NIH support as Public or Private
Institutions of Higher Education:

Non-domestic (non-U.S.) Entities (Foreign Institutions) are
not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible
to apply.
Foreign components, as defined in
the NIH Grants Policy Statement, are not allowed.

Required
Registrations

Applicant
Organizations

Applicant organizations must complete and maintain the
following registrations as described in the SF 424 (R&R) Application Guide
to be eligible to apply for or receive an award. All registrations must be
completed prior to the application being submitted. Registration can take 6
weeks or more, so applicants should begin the registration process as soon as
possible. The NIH
Policy on Late Submission of Grant Applications states that failure to
complete registrations in advance of a due date is not a valid reason for a
late submission.

Dun and Bradstreet Universal
Numbering System (DUNS) - All registrations require that applicants be
issued a DUNS number. After obtaining a DUNS number, applicants can begin both
SAM and eRA Commons registrations. The same DUNS number must be used for all
registrations, as well as on the grant application.

System for Award Management (SAM) (formerly CCR) – Applicants must complete and maintain an active registration, which requires renewal at least
annually. The renewal process may require as much time as the
initial registration. SAM registration includes the assignment of a Commercial
and Government Entity (CAGE) Code for domestic organizations which have not
already been assigned a CAGE Code.

eRA Commons - Applicants
must have an active DUNS number and SAM registration in order to complete the
eRA Commons registration. Organizations can register with the eRA Commons as
they are working through their SAM or Grants.gov registration. eRA Commons
requires organizations to identify at least one Signing Official (SO) and at
least one Program Director/Principal Investigator (PD/PI) account in order to
submit an application.

Grants.gov – Applicants
must have an active DUNS number and SAM registration in order to complete the
Grants.gov registration.

Program
Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account.
PD(s)/PI(s) should work with their organizational officials to either
create a new account or to affiliate their existing account with the applicant
organization in eRA Commons. If the PD/PI is also the organizational Signing Official,
they must have two distinct eRA Commons accounts, one for each role. Obtaining
an eRA Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal
Investigator)

Any individual(s) with the skills, knowledge, and resources
necessary to carry out the proposed research as the Program Director(s)/Principal
Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to
develop an application for support. Individuals from underrepresented racial
and ethnic groups as well as individuals with disabilities are always
encouraged to apply for NIH support.

The NIH will not accept duplicate or highly overlapping
applications under review at the same time. This means that the NIH will
not accept:

A new (A0) application that is submitted before issuance of the
summary statement from the review of an overlapping new (A0) or resubmission
(A1) application.

A resubmission (A1) application that is submitted before issuance
of the summary statement from the review of the previous new (A0) application.

An application that has substantial overlap with another
application pending appeal of initial peer review (see NOT-OD-11-101).

Only one application per institution
(normally identified by having a unique DUNS number or NIH IPF number) is
allowed. The NIH will make a single award.

Awards for a hub and a Clinical Coordinating Center (CCC, RFA-NS-19-023 ) or
Data Coordinating Center (DCC, RFA NS-19-024) may be made to the same
institution. There must be different PDs/PIs leading the hub and the CCC or
DCC to ensure that each activity receives full attention.

Section IV. Application and Submission Information

1. Requesting an
Application Package

Buttons to access the online ASSIST system or to download
application forms are available in Part
1 of this FOA. See your administrative office for instructions if you plan
to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the Research (R) Instructions
in the SF424
(R&R) Application Guide, except where instructed in this funding
opportunity announcement to do otherwise. Conformance to the requirements in
the Application Guide is required and strictly enforced. Applications that are
out of compliance with these instructions may be delayed or not accepted for
review.

Although a letter of intent is not required, is not binding,
and does not enter into the review of a subsequent application, the information
that it contains allows IC staff to estimate the potential review workload and
plan the review.

By the date listed in Part 1. Overview
Information, prospective applicants are asked to submit a letter of intent
that includes the following information:

All page limitations described in the SF424 Application
Guide and the Table of
Page Limits must be followed. for this specific FOA, the Research Strategy
section is limited to 30 pages.

Instructions for Application Submission

The following section supplements the instructions found in
the SF424 (R&R) Application Guide and should be used for preparing an
application to this FOA.

SF424(R&R) Cover

All instructions in the SF424 (R&R) Application Guide
must be followed.

SF424(R&R) Project/Performance Site Locations

All instructions in the SF424 (R&R) Application Guide
must be followed.

SF424(R&R) Other Project Information

All instructions in the SF424 (R&R) Application Guide
must be followed.

SF424(R&R) Senior/Key Person Profile

All instructions in the SF424 (R&R) Application Guide
must be followed.

The PD/PI for the hub will be a clinical trials expert with
a track record of successfully implementing clinical trials. The PD/PI for
the hub will have knowledge of and familiarity with a specific pain condition.
As support, applicants should provide evidence to demonstrate experience in:

- Working with clinicians who have access and expertise in
characterizing patients with specific pain = conditions;

- Conducting clinical trials or biomarker validation
studies;

- Contributing to leadership of a multicenter clinical
trial;

- Establishing and/or contributing to leadership of or a
network of satellite or affiliated clinical centers;

- Encouraging and implementing innovative methods to reduce
clinical trial duration and cost and to increase trial quality at their site;

- Contributing to Steering Committees or comparable
governance committees; and

- Working in a highly collaborative setting.

Applicants are strongly encouraged to name an experienced
research team. The applicants are encouraged to assemble a diverse team that
includes women and minorities. The applicants are also encouraged to
include young investigators or junior faculty, if appropriate. Members of
the research team are determined by the applicant, but often may include:

- Experienced study coordinator (s) and/or study
nurses(s). At least one of these individuals should be sufficiently
experienced to serve as a resource and guide for the spokes;

- Other research physicians;

- Experienced recruitment coordinator or specialist; and

- Experienced data management coordinator or specialist.

R&R or Modular Budget

All instructions in the SF424 (R&R) Application Guide
must be followed.

Budget requests may include the following allowable items:

- The budget submitted for this FOA should reflect baseline
costs needed to initiate, organize and maintain the hub in readiness for rapid
implementation of clinical trials.

- Partial support for the PD/PI(s) salary but ONLY for time
spent on site organizational/administrative tasks or the
EPPIC-Net governance activities;

- Salary support for full or part-time research nurses,
administrative personnel, and study assistants;

- Any physician, nurse or personnel compensation beyond that
described above. Funds for tasks specific to conduct of a specific clinical
trial, since these will be awarded separately in the grant for that individual
clinical trial.

R&R Subaward Budget

All instructions in the SF424 (R&R) Application Guide
must be followed.

PHS 398 Cover Page Supplement

All instructions in the SF424 (R&R) Application Guide
must be followed.

PHS 398 Research Plan

All instructions in the SF424 (R&R) Application Guide
must be followed, with the following additional instructions:

Research
Strategy: The Research Strategy must consist of the following
Sections A – E. Information should be presented in a manner which clearly
delineates experience and capabilities for the hub itself and the hub with
its proposed spoke network.

A) Background and Experience

The applicant should include a description of current and up to 10 recently
completed clinical trials, without duplicating information in the biosketches.
The most informative and relevant examples would be multisite phase 2 clinical
trials, or clinical trials focused on the pain treatments. The summary may
however include clinical trials on any disease from any funding source, if
judged informative by the applicant. The following metrics should be presented
in tabular form for each clinical trial:

The role of the hub and proposed research team should be clear. Published
manuscripts that highlight recently coordinated trials should be referenced in
the application in the in the Bibliography and References Cited section of the
application.

B) Leadership

Demonstration of leadership capability is required for the hub PI(s), and
should cover the specific points outlined in the Senior/Key Person Profile. It
is also expected that, in order to successfully lead a group of spokes and pre-hospital
providers, the PD/PI already plays a leadership role in some capacity to the
pain medicine community or local medical community, which should also be
described in the application.

- Leadership derives not only from the hub PD/PI, but also
from members of the hub research team. - - A brief leadership plan should
be presented which identifies and describes the roles of hub personnel, along
with how they will contribute to the success of EPPIC-Net including in the
design of phase 2 trials of drugs and devices in deeply phenotyped cohorts with
specific pain conditions.

- A brief leadership plan should be presented, including a
succession plan with identification of a substitute/back-up PD/PI candidate, if
possible, to assure programmatic continuity.

- Applicants should state their general support of
collaborative research and their willingness to participate in a collaborative
and interactive manner in all aspects of EPPIC-Net.

- Applicants should comment on any special expertise or
unique strengths they can offer to the collaborative effort.

C) Research Program

The application should:

- Present evidence of their experience in designing clinical
trial protocols, especially those focused on pain;

- Present the data demonstrating the capability of the hub
and any identified spokes to recruit, maintain, and characterize (“phenotype”)
a patient population with a specific pain condition.

- Present their concept for a hub and spoke network, and
discuss its capabilities and merits, along with attaining the flexibility and
scalability for the range of clinical trial challenges presented in hubs:
Characteristics, Roles and Responsibilities.

- Describe how the hub PD(s)/PI(s) will identify, recruit
and manage spokes. The application should include: 1) identity of 2-10
spokes committed to participation in at least one clinical trial; 2) approaches
to optimizing the spoke network for individual trials; 3) plans for
identifying, recruiting and selecting additional spokes, as needed; 4)
procedures for adding a spoke. The applicant should discuss how they plan to
make the spoke network flexible and scalable to meet potential challenges.

- Describe how the hub PD/PI will identify, recruit and
manage spoke sites. The application should include: 1) identity of at least one
spoke site committed to participate in EPPIC-Net; 2) plans for identifying,
recruiting and selecting additional spoke sites, as needed; 3) procedures for
adding a spoke site.

- Present data demonstrating the capability of the hub and
spokes to achieve an enrollment commitment of up to 100 patients per year
(assuming five on-going studies).

- Identify a committed group of multidisciplinary
professionals at the hub and committed spokes appropriate for performance of
phase II clinical trials in pain conditions.

- Specific clinical trials may require participation of
other disease experts and/or subspecialists, including but not limited to
experts in neurology, anesthesiology, rheumatology, obstetrics/gynecology,
pediatrics, orthopedics, physical medicine, gastroenterology, or other
subspecialties providing care to patients with pain. Applicants should describe
1) the potential pool of disease experts and subspecialists; 2) plans for
outreach, recruitment, collaboration and integration of disease experts/subspecialists;
3) plans to motivate disease experts to support recruitment and engage in hub
activities. 4) collaborative infrastructure that would enable
multidisciplinary involvement in EPPIC-net.

- Include any particular experience with or proposals for
innovative methods to reduce clinical trial duration and cost, and to increase
trial quality. Proposals for utilization of novel methods in EPPIC-Net are
encouraged.

- Present evidence that their hub and spoke configuration
contains the appropriate expertise and clinical population to execute clinical
trials related to low back pain.

D. Organization and Operations.

- The duties of proposed personnel responsible for day to
day administration and operations at the hub and committed spokes should be
described.

- If there is prior experience operating as a team,
this should be described.

- See Senior/Key Person Profile, for additional
descriptions of the research team.

- EPPIC-Net intends to use master contracts, centralized
trial budget estimation and payment on a per-patient basis. Institutional
acceptability and experience with these approaches should be addressed for the
hub and committed spokes.

- Responsible personnel and procedures for negotiation
and maintenance of master contracts should be identified.

- EPPIC-Net plans to establish a central IRB at the CCC, and
requires hubs and spokes to use this central IRB to facilitate clinical trial
initiation. Institutional acceptability and experience with central IRBs should
be addressed for the hub and committed spokes,

- Responsible personnel and procedures for
negotiation and maintenance of reliance agreements should be identified.

- The application should delineate the organization and
operations of the hub itself as a clinical center. The applicant should be
specific. Examples of relevant information include though are not limited to:

- The application should present the organization and
operations of the hub/spoke complex. Examples of topics include: 1)
communication with the spoke PDs/PIs and research staff; 2) training spoke
PDs/PIs and research staff on EPPIC-Net processes; 3) harmonizing or qualifying
standard operating procedures; 4) motivation and incentives for participation
and enrollment; 5) mechanisms for oversight of spoke performance; 6) mechanisms
for improving spoke performance, if needed.

E. Quality Assurance

- A specific plan for quality assurance and improvement
should be provided for the hub, including metrics, responsible personnel, and
mechanisms for collecting data and for implementing improvement plans.

- Describe how the spokes will be integrated into quality
assurance.

- The applicant should discuss results of prior site audits
at the hub or committed spokes, if available, and implementation of any
responsive improvement plan. Relevant audits relate to clinical research
and may have been conducted by NIH, FDA or industry

Letters
of Support

A statement of commitment from each participating
institution or organization must be provided. In addition, an institutional
letter of support from the applicant's departmental and/or institutional
leadership must be included in the application. It should address how the
institutional commitment will be established and sustained, how the institution
will maintain accountability for promoting scientific excellence, and how the EPPIC-Net
effort will be given a high priority within the institution (relative to other
research efforts and non-NIH supported programs.) The institutional commitment
may be in the form of support for recruitment of scientific talent, provision
of discretionary resources to the network site director, assignment of
specialized research space, cost sharing of resources, and/or other ways
proposed by the applicant institution. Letters from a high-level institution
official(s) (e.g., Dean of the School of Medicine, Hospital President, and Vice
President for Research) should be included confirming this commitment.

A statement of commitment to participate in EPPIC-Net should be provided from
the spoke sites. These letters should include description of particular
resources to be committed, relevant prior experience, planned organizational
and/or administrative structure in conjunction with the hub, and willingness to
participate collaboratively in the broader EPPIC-Net structure (e.g., central
IRB, master contracts).

For those institutions with a Clinical Translational Science Award (CTSA), the
applicants are encouraged to include documentation from the CTSA principal
investigator regarding any support which will be provided to the hub. This may
include access to or assistance from Recruitment (RIC) and Trial (TIC)
liaisons at the CTSA.

Additional letters of support may be included from key personnel, such as
disease experts and physician subspecialists.

Resource
Sharing Plan: Individuals are required to comply with the
instructions for the Resource Sharing Plans as provided in the SF424 (R&R)
Application Guide, with the following modification:

· All applications, regardless of the amount of direct costs
requested for any one year, should address a Data Sharing Plan.

Appendix:

Only limited Appendix materials are allowed. Follow all
instructions for the Appendix as described in the SF424 (R&R) Application
Guide.

PHS Human Subjects and Clinical Trials Information

When involving NIH-defined human subjects research, clinical
research, and/or clinical trials (and when applicable, clinical trials research
experience) follow all instructions for the PHS Human Subjects and Clinical
Trials Information form in the SF424 (R&R) Application Guide, with the following
additional instructions:

If you answered “Yes” to the question “Are Human Subjects
Involved?” on the R&R Other Project Information form, you must include at
least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials
Information form or Delayed
Onset Study record.

Study
Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide
must be followed with the following additional instructions:

Delayed
Onset Study

All instructions in the SF424 (R&R) Application Guide
must be followed.

PHS Assignment Request Form

All instructions in the SF424 (R&R) Application Guide
must be followed.

3. Unique Entity Identifier
and System for Award Management (SAM)

See Part 1. Section III.1 for information regarding the
requirement for obtaining a unique entity identifier and for completing and
maintaining active registrations in System for Award Management (SAM), NATO
Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and
Grants.gov

4. Submission Dates and
Times

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to
submit applications before the due date to ensure they have time to make any
application corrections that might be necessary for successful submission. When
a submission date falls on a weekend or Federal
holiday, the application deadline is automatically extended to the next
business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants
across all Federal agencies). Applicants must then complete the submission
process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants
administration. NIH and Grants.gov systems check the application against many
of the application instructions upon submission. Errors must be corrected and a
changed/corrected application must be submitted to Grants.gov on or before the application
due date and time. If a Changed/Corrected application is submitted after the
deadline, the application will be considered late. Applications that miss the
due date and time are subjected to the NIH Policy on Late Application
Submission.

Applicants
are responsible for viewing their application before the due date in the eRA
Commons to ensure accurate and successful submission.

Information on the submission process and a definition of
on-time submission are provided in the SF424 (R&R) Application Guide.

For assistance with your electronic application or for more information on the electronic submission
process, visit Applying
Electronically. If you encounter a system issue beyond your control that
threatens your ability to complete the submission process on-time, you must
follow the Guidelines
for Applicants Experiencing System Issues. For assistance with application
submission, contact the Application Submission Contacts in Section VII.

Important
reminders:

All PD(s)/PI(s) must include their eRA Commons ID in
the Credential fieldof the Senior/Key Person Profile Component of the
SF424(R&R) Application Package. Failure to register in the Commons
and to include a valid PD/PI Commons ID in the credential field will prevent
the successful submission of an electronic application to NIH. See Section III of this FOA for information on
registration requirements.

The applicant organization must ensure that the DUNS
number it provides on the application is the same number used in the
organization’s profile in the eRA Commons and for the System for Award Management.
Additional information may be found in the SF424 (R&R) Application Guide.

Upon receipt, applications will be evaluated for
completeness and compliance with application instructions by the Center for
Scientific Review and responsiveness by components
of participating organizations, NIH. Applications that are incomplete, non-compliant
and/or nonresponsive will not be reviewed.

Post Submission Materials

Applicants are required to follow the instructions for
post-submission materials, as described in the policy.
Any instructions provided here are in addition to the instructions in the
policy.

Section V. Application Review Information

1.
Criteria

Only the review criteria described below will be considered
in the review process. As part of the NIH mission,
all applications submitted to the NIH in support of biomedical and behavioral
research are evaluated for scientific and technical merit through the NIH peer
review system.

Overall Impact

Reviewers will provide an overall impact score to reflect
their assessment of the likelihood for the project to exert a sustained,
powerful influence on the research field(s) involved, in consideration of the
following review criteria and additional review criteria (as applicable for the
project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in
the determination of scientific merit, and give a separate score for each. An
application does not need to be strong in all categories to be judged likely to
have major scientific impact. For example, a project that by its nature is not
innovative may be essential to advance a field.

Significance

Does the project address an
important problem or a critical barrier to progress in the field? Is the prior
research that serves as the key support for the proposed project rigorous? If
the aims of the project are achieved, how will scientific knowledge, technical
capability, and/or clinical practice be improved? How will successful
completion of the aims change the concepts, methods, technologies, treatments,
services, or preventative interventions that drive this field?

How will the proposed hub
contribute to the advancement of clinical research in pain and clinical trials
with the framework of EPPIC-Net?

Investigator(s)

Are the PD(s)/PI(s), collaborators,
and other researchers well suited to the project? If Early Stage Investigators
or those in the early stages of independent careers, do they have appropriate
experience and training? If established, have they demonstrated an ongoing
record of accomplishments that have advanced their field(s)? If the project is
collaborative or multi-PD/PI, do the investigators have complementary and
integrated expertise; are their leadership approach, governance and
organizational structure appropriate for the project?

Do the PD(s)/PI(s), collaborators,
and other researchers demonstrate a familiarity with clinical pain research?

Does the application indicate that
the PD/PI has the appropriate experience to prepare him/her for designing,
leading and performing clinical trials? Which components of the PD/PI's
experience prepare him/her for designing and performing early phase clinical
trials in pain medicine?

Does the application indicate that the PD/PI has prior or existing leadership
roles in the pain medicine community and/or local medical community which will
contribute to the success of EPPIC-Net?

How do the PD/PI's past experiences prepare him/her for establishing and/or
leading a network of affiliated clinical sites?

In what ways does the application suggest that the PD/PI can contribute
substantially to the EPPIC-Net governance committees (e.g., the EPPIC-Net
Steering Committee and subcommittees, the EPPIC-Net Management committee, the
EPPIC-Net Operations committee)? Does the application demonstrate that
the PD/PI will have time to attend the meetings and teleconferences?

In what way does the PD/PI's experience prepare him/her for leading and working
in highly collaborative settings?

Is there assurance that the proposed research team and administrative personnel
are qualified, capable and experienced? In what ways will they increase
the likelihood that performance will be exemplary at the proposed hub and
spokes?

Innovation

Does the application challenge and
seek to shift current research or clinical practice paradigms by utilizing
novel theoretical concepts, approaches or methodologies, instrumentation, or
interventions? Are the concepts, approaches or methodologies, instrumentation,
or interventions novel to one field of research or novel in a broad sense? Is a
refinement, improvement, or new application of theoretical concepts, approaches
or methodologies, instrumentation, or interventions proposed?

Does this application demonstrate
that the proposed hub will participate in master contracts, centralized trial
budgeting and per patient payments, as planned in EPPIC-Net? Does this
application demonstrate that the proposed spokes will participate in master
contracts, centralized trial budgeting and per patient payments, as planned in
EPPIC-Net?

Does this application demonstrate that the proposed hub/spokes will perform
clinical trials under approval by a central IRB, as planned for EPPIC-Net?

Does the application provide evidence to suggest that the PD/PI or other
members of the proposed research team could institute novel and innovative
procedures that would increase efficiency and/or quality of clinical trial
conduct in the network, at the hub and/or its affiliated spokes? Does the
application provide evidence to suggest that the PD/PI, through participation
in the EPPIC-Net governance committees, could provide innovative ideas to
increase efficiency and/or quality of clinical trial conduct throughout
EPPIC-Net?

Approach

Are the overall strategy,
methodology, and analyses well-reasoned and appropriate to accomplish the
specific aims of the project? Have the investigators included plans to address
weaknesses in the rigor of prior research that serves as the key support for
the proposed project? Have the investigators presented strategies to ensure a
robust and unbiased approach, as appropriate for the work proposed? Are
potential problems, alternative strategies, and benchmarks for success
presented? If the project is in the early stages of development, will the
strategy establish feasibility and will particularly risky aspects be managed? Have
the investigators presented adequate plans to address relevant biological variables,
such as sex, for studies in vertebrate animals or human subjects?

To what extent do data in the
application (e.g., prior clinical trial performance; catchment area) support
the ability of this hub and its spokes to enroll a substantial number of
subjects per year? To contribute to enrollment goals for minorities, gender, or
other underserved groups (e.g., rural patients)? Does this application
lend assurance that the proposed hub/spoke group will be able to contribute to
clinical trials in the planned range of pain disorders and associated
conditions, especially chronic low back pain? How strong are the letters of
support and commitment?

To what extent does the resultant hub/committed spoke network fulfill the
characteristics outlined in "Clinical hubs: Characteristics, Roles and
Responsibilities"?

In what ways does the application lend assurance that the applicant can tailor
spokes to the needs of each trial, which include:
1) execute phase 2 trials in various settings, including out-patient clinics in
several specialties;
2) provide and coordinate the multiple medical specialties which may
participate in the trials; and
3) propose and oversee a network of spokes. (see examples above in
"Clinical hubs: Characteristics, Roles and Responsibilities")?

In what ways does the organization plan promote communication and
collaboration:
1) among research personnel at the hub;
2) with disease experts; and
3) between the hub and spokes?

Does the application support that the operational procedures and quality
assurance program will lead to exemplary trial execution? To what
extent does the evidence in the application demonstrate that the hub and
committed spokes can and will consistently deliver high quality clinical trial
performance? Were findings from prior audits (if any) appropriately resolved?

If the project involves human
subjects and/or NIH-defined clinical research, are the plans to address 1) the
protection of human subjects from research risks, and 2) inclusion (or
exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as
well as the inclusion or exclusion of individuals of all ages (including children
and older adults), justified in terms of the scientific goals and research
strategy proposed?

How will the hubs and spokes
solicit additional content matter expertise when needed?

Environment

Will the scientific environment in
which the work will be done contribute to the probability of success? Are the
institutional support, equipment and other physical resources available to the
investigators adequate for the project proposed? Will the project benefit from
unique features of the scientific environment, subject populations, or
collaborative arrangements?

In the letters of support and
commitment, does the institution demonstrate appropriate commitment for the
PD/PI (may be expressed as additional protected time, departmental research
leadership position, facilities, space, or resources)?

As applicable for the project proposed, reviewers will
evaluate the following additional items while determining scientific and
technical merit, and in providing an overall impact score, but will not give
separate scores for these items.

Protections for Human Subjects

For research that involves human
subjects but does not involve one of the categories of research that are exempt
under 45 CFR Part 46, the committee will evaluate the justification for
involvement of human subjects and the proposed protections from research risk
relating to their participation according to the following five review
criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3)
potential benefits to the subjects and others, 4) importance of the knowledge
to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human
subjects and meets the criteria for one or more of the categories of research
that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the
justification for the exemption, 2) human subjects involvement and
characteristics, and 3) sources of materials. For additional information on
review of the Human Subjects section, please refer to the Guidelines for the Review of Human
Subjects.

Inclusion of Women, Minorities,
and Individuals Across the Lifespan

When the proposed project involves
human subjects and/or NIH-defined clinical research, the committee will evaluate
the proposed plans for the inclusion (or exclusion) of individuals on the basis
of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals
of all ages (including children and older adults) to determine if it is
justified in terms of the scientific goals and research strategy proposed. For
additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion
in Clinical Research.

Vertebrate Animals

The committee will evaluate the
involvement of live vertebrate animals as part of the scientific assessment
according to the following criteria: (1) description of proposed procedures
involving animals, including species, strains, ages, sex, and total number to
be used; (2) justifications for the use of animals versus alternative models
and for the appropriateness of the species proposed; (3) interventions to
minimize discomfort, distress, pain and injury; and (4) justification for
euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia
of Animals. Reviewers will assess the use of chimpanzees as they would any
other application proposing the use of vertebrate animals. For additional information
on review of the Vertebrate Animals section, please refer to the Worksheet
for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether
materials or procedures proposed are potentially hazardous to research
personnel and/or the environment, and if needed, determine whether adequate
protection is proposed.

Resubmissions

N/A

Renewals

N/A

Revisions

N/A

Additional Review Considerations

As applicable for the project proposed, reviewers will
consider each of the following items, but will not give scores for these items,
and should not consider them in providing an overall impact score.

Applications from Foreign
Organizations

N/A

Select Agent Research

Reviewers will assess the
information provided in this section of the application, including 1) the
Select Agent(s) to be used in the proposed research, 2) the registration status
of all entities where Select Agent(s) will be used, 3) the procedures that will
be used to monitor possession use and transfer of Select Agent(s), and 4) plans
for appropriate biosafety, biocontainment, and security of the Select Agent(s).

For projects involving key biological and/or chemical resources,
reviewers will comment on the brief plans proposed for identifying and ensuring
the validity of those resources.

Budget and Period of Support

Reviewers will consider whether the
budget and the requested period of support are fully justified and reasonable
in relation to the proposed research.

2. Review and Selection
Process

Applications will be evaluated for scientific and technical
merit by (an) appropriate Scientific Review Group(s) convened by NINDS, in
accordance with NIH peer
review policy and procedures, using the stated review
criteria. Assignment to a Scientific Review Group will be shown in the eRA
Commons.

As part of the scientific peer review, all applications:

· May undergo a selection process in which only those applications
deemed to have the highest scientific and technical merit (generally the top
half of applications under review) will be discussed and assigned an overall impact
score.

Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in
response to this FOA.

Applications will be assigned on the basis of established
PHS referral guidelines to the appropriate NIH Institute or Center. Applications
will compete for available funds with all other recommended applications submitted
in response to this FOA. Following initial peer review, recommended applications
will receive a second level of review by the appropriate national Advisory
Council or Board. The following will be considered in making funding decisions:

Scientific and technical merit of the proposed project as determined by
scientific peer review.

Availability of funds.

Relevance of the proposed project to program priorities.

· Clinical trial expertise, track record, and resources.

· Strong track record of successful collaboration and participation
in large, multi-center research teams and willingness to work collaboratively,
including with other components of the EPPIC-Net.

· Ability to begin operations on the "Earliest Start
Date" listed in this FOA (Section II.1).

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the
PD/PI will be able to access his or her Summary Statement (written critique)
via the eRA
Commons. Refer to Part 1 for dates for peer review, advisory council
review, and earliest start date.

If the application is under consideration for funding, NIH
will request "just-in-time" information from the applicant as
described in the NIH
Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA)
will be provided to the applicant organization for successful applications. The
NoA signed by the grants management officer is the authorizing document and
will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described
in Section IV.5. Funding Restrictions. Selection
of an application for award is not an authorization to begin performance. Any
costs incurred before receipt of the NoA are at the recipient's risk. These
costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be
subject to terms and conditions found on the Award
Conditions and Information for NIH Grants website. This includes any
recent legislation and policy applicable to awards that is highlighted on this
website.

Recipients of federal financial
assistance (FFA) from HHS must administer their programs in compliance with
federal civil rights law. This means that recipients of HHS funds must ensure
equal access to their programs without regard to a person’s race, color,
national origin, disability, age and, in some circumstances, sex and religion.
This includes ensuring your programs are accessible to persons with limited
English proficiency. HHS recognizes that research projects are often limited
in scope for many reasons that are nondiscriminatory, such as the principal
investigator’s scientific interest, funding limitations, recruitment
requirements, and other considerations. Thus, criteria in research protocols
that target or exclude certain populations are warranted where
nondiscriminatory justifications establish that such criteria are appropriate
with respect to the health or safety of the subjects, the scientific study
design, or the purpose of the research.

For additional guidance regarding how the provisions apply
to NIH grant programs, please contact the Scientific/Research Contact that is
identified in Section VII under Agency Contacts of this FOA. HHS provides
general guidance to recipients of FFA on meeting their legal obligation to take
reasonable steps to provide meaningful access to their programs by persons with
limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html.
The HHS Office for Civil Rights also provides guidance on complying with civil
rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html;
and http://www.hhs.gov/ocr/civilrights/understanding/index.html.
Recipients of FFA also have specific legal obligations for serving qualified
individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html.
Please contact the HHS Office for Civil Rights for more information about
obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS
Departmental goal to ensure access to quality, culturally competent care,
including long-term services and supports, for vulnerable populations. For further
guidance on providing culturally and linguistically appropriate services,
recipients should review the National Standards for Culturally and
Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

In accordance with the statutory provisions contained in
Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal
Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal
Awardee Performance and Integrity Information System (FAPIIS) requirements.
FAPIIS requires Federal award making officials to review and consider
information about an applicant in the designated integrity and performance
system (currently FAPIIS) prior to making an award. An applicant, at its
option, may review information in the designated integrity and performance
systems accessible through FAPIIS and comment on any information about itself
that a Federal agency previously entered and is currently in FAPIIS. The
Federal awarding agency will consider any comments by the applicant, in
addition to other information in FAPIIS, in making a judgement about the
applicant’s integrity, business ethics, and record of performance under Federal
awards when completing the review of risk posed by applicants as described in
45 CFR Part 75.205 “Federal awarding agency review of risk posed by
applicants.” This provision will apply to all NIH grants and cooperative agreements
except fellowships.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and
not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB)
administrative guidelines, U.S. Department of Health and Human Services (DHHS)
grant administration regulations at 45 CFR Part 75(Part 92 is applicable when
State and local Governments are eligible to apply), and other HHS, PHS, and NIH
grant administration policies. The administrative and funding instrument used
for this program will be the cooperative agreement, an "assistance"
mechanism (rather than an "acquisition" mechanism), in which
substantial NIH programmatic involvement with the awardees is anticipated
during the performance of the activities. Under the cooperative agreement, the
NIH purpose is to support and stimulate the recipients' activities by
involvement in and otherwise working jointly with the award recipients in a
partnership role; it is not to assume direction, prime responsibility, or a
dominant role in the activities. Consistent with this concept, the dominant
role and prime responsibility resides with the awardees for the project as a
whole, although specific tasks and activities may be shared among the awardees
and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

- Trial participant safety, implementation of network
protocols in accordance with GCP and other regulatory requirements, participant
recruitment and retention, reporting to the CCC, DCC, central IRB and DSMB.

- Awardees will retain custody of and have primary rights to
the data and software developed under these awards, subject to Government
rights of access consistent with current DHHS, PHS, and NIH policies. The
owners of candidate therapeutics (“assets”) that undergo clinical testing
through EPPIC-Net will retain the intellectual property rights to their asset.

NIH staff have substantial programmatic involvement that is
above and beyond the normal stewardship role in awards, as described below:

- The NIH staff in collaboration with the EPPIC-Net Federal
Committee will work with the EPPIC-Net investigators to develop performance
milestones for the CCC. Failure to meet the agreed upon milestones may result
in reduced funding or early termination of the cooperative agreement

- An NIH Project Scientist will have substantial
programmatic involvement that is above and beyond the normal stewardship role
in awards:

- Cooperation or coordination with, or assistance to,
awardees in performing project activities, e.g., development of research
protocols; data collection, analyses, and interpretations; re-establishment of
objectives during the course of a project;

- Providing for an option to halt a project activity if
technical performance requirements are not met or if program objectives have
already been met;

- Assistance with the selection of contractors or
sub-awardees and in the selection of key project personnel other than PD/PI;

- Technical monitoring to permit specific direction of
the project, including recommending approval of changes in technical
approaches;

- Participation on committees as a voting member
or in other functions responsible for helping to guide the course of EPPIC-Net;
and

- Participation in the presentation of research
results, including publications from the project.

- In addition to the Project Scientist, an NIH Program
Official will be responsible for the normal programmatic stewardship of the
award and will be named in the award notice.

The release of funds will be milestone-driven. Milestones
will be determined jointly by the awardee, NINDS and the EPPIC-Net Federal
Committee after the grant has been awarded and will be specified in the Notice
of Award. The following are illustrative potential milestones for the first
year of the award:

- Formation of a network of spokes;

- Completion of reliance agreements for central IRB;

- Completion of master contracts.

When phase 2 trials are being conducted in EPPIC-Net,
milestones will be reflective of enrollment and timely provision of
high-quality trial data.

The hubs must achieve their agreed milestones during the first year in order to
be eligible for future years of funding. hubs that do not meet agreed
milestones for any year of the grant term may be terminated, if
necessary. In addition, awards may be restricted at sites unable to
successfully participate in the EPPIC-Net clinical trials (e.g., inadequate
patient enrollment, unacceptable ratings on quality metrics) or unsupportive of
broader EPPIC-Net functions (e.g., failure to participate in governance).

Dispute Resolution:

Any disagreements that may arise in scientific or
programmatic matters (within the scope of the award) between award recipients
and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel
composed of three members will be convened. It will have three members: a
designee of the Steering Committee chosen without NIH staff voting, one NIH
designee, and a third designee with expertise in the relevant area who is
chosen by the other two; in the case of individual disagreement, the first
member may be chosen by the individual awardee. This special dispute resolution
procedure does not alter the awardee's right to appeal an adverse action that
is otherwise appealable in accordance with PHS regulation 42 CFR Part 50,
Subpart D and DHHS regulation 45 CFR Part 16.

A final RPPR, invention statement,
and the expenditure data portion of the Federal Financial Report are required for
closeout of an award, as described in the NIH
Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of
2006 (Transparency Act), includes a requirement for awardees of Federal grants
to report information about first-tier subawards and executive compensation
under Federal assistance awards issued in FY2011 or later. All awardees of
applicable NIH grants and cooperative agreements are required to report to
the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH
Grants Policy Statement for additional information on this reporting
requirement.

In accordance with the regulatory requirements provided at
45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have
currently active Federal grants, cooperative agreements, and procurement
contracts from all Federal awarding agencies with a cumulative total value
greater than $10,000,000 for any period of time during the period of
performance of a Federal award, must report and maintain the currency of
information reported in the System for Award Management (SAM) about civil,
criminal, and administrative proceedings in connection with the award or
performance of a Federal award that reached final disposition within the most
recent five-year period. The recipient must also make semiannual
disclosures regarding such proceedings. Proceedings information will be
made publicly available in the designated integrity and performance system
(currently FAPIIS). This is a statutory requirement under section 872 of
Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010
of Public Law 111-212, all information posted in the designated integrity and
performance system on or after April 15, 2011, except past performance reviews
required for Federal procurement contracts, will be publicly available. Full
reporting requirements and procedures are found in Appendix XII to 45 CFR Part
75 – Award Term and Conditions for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity
and welcome the opportunity to answer questions from potential applicants.